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Cre recombinase toxicity in podocytes: a novel genetic model for FSGS in adolescent mice
Madeleine Frahsek1, Kevin Schulte1,2, Arnaldo Chia-Gil1
1Nephrology and Clinical Immunology, University Hospital of RWTH Aachen University, Aachen, Germany.
Abstract:
Here, we show that inducible overexpression of Cre recombinase in glomerular podocytes but not in parietal epithelial cells may trigger focal segmental glomerulosclerosis (FSGS) in juvenile transgenic homocygous Pod-rtTA/LC1 mice. Administration of doxycycline shortly after birth, but not at any other time point later in life, resulted in podocyte injury and development of classical FSGS lesions in these mice. Sclerotic lesions were formed as soon as 3 wk of age, and FSGS progressed with low variability until 13 wk of age. In addition, our experiments identified Cre toxicity as a potentially relevant limitation for studies in podocytes of transgenic animals. In summary, our study establishes a novel genetic model for FSGS in mice, which exhibits low variability and manifests already at a young age.
Insights
Inducible Cre recombinase in podocytes triggers focal segmental glomerulosclerosis (FSGS) in juvenile mice. Early doxycycline administration caused FSGS lesions, highlighting a new genetic model for this kidney disease.
Area of Science:
- Nephrology
- Genetics
- Molecular Biology
Background:
- Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease.
- Understanding the genetic and molecular mechanisms of FSGS is crucial for developing effective treatments.
Purpose of the Study:
- To establish a novel inducible genetic mouse model for studying FSGS.
- To investigate the role of Cre recombinase in podocyte injury and FSGS development.
Main Methods:
- Utilized transgenic mice (Pod-rtTA/LC1) with inducible Cre recombinase expression in podocytes.
- Administered doxycycline post-birth to trigger Cre expression and observed subsequent kidney pathology.
Main Results:
- Inducible Cre overexpression in podocytes, but not parietal epithelial cells, induced FSGS lesions in juvenile mice.
- Early doxycycline administration led to podocyte injury and progressive FSGS development with low variability.
- Cre toxicity was identified as a potential confounding factor in transgenic mouse studies.
Conclusions:
- A novel, low-variability, early-onset genetic mouse model for FSGS has been established.
- This model provides a valuable tool for investigating FSGS pathogenesis and therapeutic strategies.
- The findings underscore the importance of considering Cre toxicity in transgenic research.
